1. Field of the Invention
The subject matter of this application relates to the preparation of novel magnesium phosphates (MGP) and their exploitation in the medical field, to-wit, their use in recirculating dialysis systems and other systems having the purpose of removing urea/ammonia from body fluids and in waste water treatment to remove ammonium ions (NH.sub.4.sup.+). As one of the embodiments of the invention, the novel magnesium phosphate product can be utilized as a replacement for the older zirconium phosphate (ZP) materials which in combination with an artificial kidney can be used to effect removal of urea/ammonia from the dialysate solution employed within the artificial kidney prior to the dialysate solution being reconducted through the artificial kidney. The instant invention also relates to the field of encapsulated medical products for human consumption in eliminating urea present in the gastrointestinal tract.
2. Description of the Prior Art and Other Information
Urea is present in blood, intestinal contents and other body fluids of normal as well as uremic patients. Uremia is a clinical term describing the condition in which the level of urea in a patient's blood is elevated above the normal levels of about 20 to about 40 milligrams per deciliter (mg/dl). Uremia is due to the nephron function being inadequate to excrete the urea generated by protein metabolism.
Excess urea can be removed by: (1) mass transfer across a membrane from blood to another low urea content fluid as in hemodialysis; or (2) mass transfer across the membranes of the peritoneum into a low urea content fluid as in peritoneal dialysis; or (3) by strongly absorbing urea or its hydrolysis products, especially ammonia, from the intestinal tract. See Kjellstrand, infra.
In the last several decades, systems have been developed to treat people who might otherwise die of kidney failure due to the inability of the kidney to remove metabolites, e.g., urea/ammonia from the blood and other body tissues and organs. By the removal of "urea/ammonia from the blood and other body tissues and organs", we mean more precisely the removal of ammonium ions from solution, the source of these NH.sub.4.sup.+ ions being the hydrolysis of urea, either catalyzed by an exogenous urease enzyme such as jack bean meal urease or by an endogenous urease or by non-catalyzed hydrolysis of urea. Also, NH.sub.4.sup.+ is produced by bacterial activity in the intestine. Normally, this NH.sub.4.sup.+ is converted to urea by the liver. Thus, by removing NH.sub.4.sup.+ which is or is not the product of urease catalyzed hydrolysis of urea, the net effect is to reduce the amount of urea which would have to be removed by other means.
Over a period of time, variations on these basic methods of removing urea have been made. In the field of hemodialysis, artificial kidneys were developed following the initial disclosure of the first suggestion for an effective mass transfer exchanger to treat a patient's blood through mass exchange with a treating solution. See Mahon, U.S. Pat. Nos. 3,228,886 and 3,228,887.
Commencing with the pioneer invention of Marantz and co-workers of a recirculation dialysate system for use with artificial kidney machines, U.S. Pat. No. 3,669,880, much investigation and development has ensued in the marketing of various portable systems whereby artificial kidneys can be employed at locations other than the hospital in order to reduce the cost and increase convenience to the patients. See U.S. Pat. Nos. 3,697,410; 3,697,418; 3,703,959; 3,850,835; 3,989,622; 4,164,437; 4,212,738; and 4,256,718. Presently, such an advanced recirculation dialysate system for use with artificial kidneys is marketed under the trademark REDY.TM. by Organon Teknika Corporation of Oklahoma City, Okla. Following the disclosure of U.S. Pat. No. 3,332,737 to Kraus, much study has been made toward the development of materials suitable for removing metabolites, e.g., urea/ammonia from the blood and from various body tissues and organs. Early on, it was discovered that zirconium phosphate was effective for removing these metabolites. See U.S. Pat. No. 3,669,880, Column 2, lines 54-67. Of course, zirconium phosphate was old at the time of the '880 invention. F. Hevesey and K. Kimura, J. AM. CHEM. SOC., 47 at 2540, et seq., (1925) examined zirconium and hafnium phosphates looking for ways to separate them, and methods of preparation and solubility were examined. R. Ried and J. Withrow, J. AM. CHEM. SOC., 51 at 1311 (1929) did an extensive study on methods of quantitatively precipitating zirconium phosphate using various phosphate mixtures. Chemical abstracts list several references to zirconium-hafnium separations employing phosphates. Note Z. ANORG. ALLGEM. CHEM., 165 at 1-15, 21-30 (1927), U.S. Pat. No. 1,636,493 and Dutch Pat. Nos. 16,508; 16,510; 16,955, and 16,956.
The progeny of the '880 patent discloses much investigation toward the preparation of various zirconium hydrous oxide ion exchangers comprising amorphous or microcrystalline solids containing zirconium or zirconium plus other oxides of hydroxides in various amounts of water. In addition, the recirculating dialysis systems utilize disposable cartridges containing layers of urease and ZP separate from other layers of aluminum oxide and magnesium silicate. See U.S. Pat. No. 3,989,622 and FIG. No. 1 therein.
In the above cited art, '880, etc., ZP has been used as the preferred ammonia absorbant.
A very recent development to the gastrointestinal approach utilizes an enzyme urease from jack beans, encapsulated along with an ammonia absorber, ZP. The capsules are swallowed by the uremic patient and act to remove urea as ammonia. The removal of urea is completed when the capsules are voided in the patient's stools. This treatment, while not a complete replacement for dialysis, is useful to postpone the onset or reduce the number of expensive and debilitating extracorporeal treatments. See Carl M. Kjellstrand et al., "On the Clinical Use of Microencapsulated Zirconium Phosphate-Urease, the Treatment of Chronic Uremia", TRANS. AMER. SOC. ARTIF. INT. ORGANS 27 at 24-29, (1981) and the pioneering microencapsulation work of Gardner and 15 coworkers at Battelle Memorial Institute, Columbus, Ohio, in articles cited therein. In these articles, ZP is again the ammonia absorber of choice.
3. The Problems Associated with Zirconium Phosphate and Replacing It
In 1981, and at the time of this invention, more than 56,000 Americans were being kept alive by maintenance peritoneal or hemodialysis at an annual expenditure of over $1.2 billion. Because of its extraordinary cost, however, three out of four people around the world will have no chance of receiving contemporary uremia therapy should their kidneys fail. Health planners in developed countries, stressed by the advancing expense of uremia therapy, are exploring shortened, more efficient hemodialysis and/or the potential benefits of Continuous Ambulatory Peritoneal Dialysis (CAPD) to contain costs. Also, to reduce the volume and cost of dialysate fluid and to improve the mobility of hemodialysis equipment, recirculating dialysate systems have been introduced and are being used by uremic patients.
Unfortunately, however, all of these recirculation-looped, artifical kidney hemodialysis systems rely on the use of zirconium phosphate--a relatively expensive material whose precursors are only available from a few sources in the world, e.g., the Union of Soviet Socialist Republics and the Union of South Africa--presenting supply difficulties. In addition, because of its relative ineffectiveness in removing ammonia/urea from dialysis solution and body cavities, i.e., because of its nonspecificity and limited binding capacity for NH.sub.4.sup.+, ZP has had to be employed in relatively great quantities and has even been shown to remove serum potassium, calcium, and magnesium during microencapsulation treatment. Removing potassium and calcium from patients is detrimental because (1) potassium is needed by the patient for proper sodium/potassium balance; (2) calcium loss is increased in uremic patients due to accumulated phosphate ion concentration. This leads to bone decalcification, a serious problem for uremic patients. See Kjellstrand, supra. Also, a large volume of ZP/urease capsules needs to be ingested by the patient because of low-binding capacity for ammonia and the low specificity for ammonium ions of the ZP material. The need to take such large quantities of this material may lead to stomach upset and the patient's refusal to adhere to this therapy regimen.
The great expense of manufacturing ZP, poor availability worldwide, and its nonspecificity have long been criticized in its use for the treatment of uremia. Notwithstanding numerous investigational studies attempting to obtain solutions to exploit alternatives to ZP in disposable cartridges and in the gut as substitute nephrons, including administration of oral sorbent and intestinal perfusion, no practical commercial successor to ZP has been found.
While it is clear that the strategies described in the preceeding background sections were, for their time, attempts to provide improved, lower cost treatment and improve the clinical course of uremic patients, it is also apparent that the use of ZP in these therapies has limited their ability to reach the goal of better patient health. In order to measurably advance the art, a successor to ZP is needed.